Many previous attempts have been made to locally administer radioactive materials to patients with cancer, as a form of therapy. In some of these, the radioactive materials have been incorporated into small particles, seeds, wires and similar related configurations that can be directly implanted into the cancer. When radioactive particles are administered into the blood supply of the target organ, the technique has become known as Selective Internal Radiation Therapy (SIRT). Generally, the main form of application of SIRT has been its use to treat cancers in the liver.
There are many potential advantages of SIRT over conventional, external beam radiotherapy. Firstly, the radiation is delivered preferentially to the cancer within the target organ. Secondly, the radiation is slowly and continually delivered as the radionuclide decays. Thirdly, by manipulating the arterial blood supply with vasoactive substances (such as Angiotensin-2), it is possible to enhance the percentage of radioactive particles that go to the cancerous part of the organ, as opposed to the healthy normal tissues. This has the effect of preferentially increasing the radiation dose to the cancer while maintaining the radiation dose to the normal tissues at a lower level (Burton, M. A. et al.; Effect of Angiotensin-2 on blood flow in the transplanted sheep squamous cell carcinoma. Europ. J. Cancer Clin. Oncol. 1988, 24(8): 1373–1376).
When microspheres or other small particles are administered into the arterial blood supply of a target organ, it is desirable to have them of a size, shape and density that results in the optimal homogeneous distribution within the target organ. If the microspheres or small particles do not distribute evenly, and as a function of the absolute arterial blood flow, then they may accumulate in excessive numbers in some areas and cause focal areas of excessive radiation. It has been shown that microspheres of approximately 25–50 micron in diameter have the best distribution characteristics when administered into the arterial circulation of the liver (Meade, V. et al.; Distribution of different sized microspheres in experimental hepatic tumours. Europ. J. Cancer & Clin. Oncol. 1987, 23:23–41).
If the microspheres or seeds do not contain sufficient ionising radiation, then an excessive number will be required to deliver the required radiation dose to the target organ. It has been shown that if large numbers of microspheres are administered into the arterial supply of the liver, then they accumulate in and block the small arteries leading to the tumour, rather than distribute evenly in the capillaries and precapillary arterioles of the tumour. Therefore, it is desirable to use the minimum number of microspheres that will provide an even distribution in the vascular network of the tumour circulation.
For radioactive microspheres to be used successfully for the treatment of cancer, the radiation emitted from the microspheres should be of high energy and short range. This ensures that the energy emitted from the microspheres will be deposited into the tissues immediately around the microspheres and not into tissues that are not the target of the radiation treatment. There are many radionuclides that can be incorporated into microspheres that can be used for SIRT. In this treatment mode, it is desirable to use microspheres or seeds that emit high energy but short penetration beta radiation that will confine the radiation effects to the immediate vicinity of the microspheres or seeds.
If the microspheres or seeds contain other radioactive substances that are not required for the radiation treatment of the target tissue or for dosimetry or imaging, then unwanted and deleterious radiation effects may occur. It is therefore desirable to have microspheres or seeds of such a composition that they primarily only contain the desired radionuclide(s).
In the earliest clinical use of yttrium-90-containing microspheres, the yttrium was incorporated into a polymeric matrix that was formulated into microspheres. While these microspheres were of an appropriate size to ensure good distribution characteristics in the liver, there were several instances in which the yttrium-90 leached from the microspheres and caused inappropriate radiation of other tissues. The other disadvantage of resin based microspheres is that production requires loading of the microspheres after the radionuclide has been formed and this results in radiation exposure to manufacturing staff. There is always the potential for these microspheres to leach the yttium-90 and the amount of yttrium-90 that can be loaded onto the resin is also limited.
In one attempt to overcome the problem of leaching, a radioactive microsphere comprising a biologically compatible glass material containing a beta or gamma radiation emitting radioisotope such as yttrium-90 distributed homogeneously throughout the glass as one of the glass component oxides, has been developed (International Patent Publication No. WO 86/03124). These microspheres are solid glass and contain the element yttrium-89 as a component of the glass, which can be activated to the radionuclide yttrium-90 by placing the microspheres in a neutron beam. These glass microspheres have several disadvantages including being of a higher density than is desirable, containing the yttrium-90 within the matrix of the microspheres as opposed to on the surface and also containing significant amounts of other elements such as glass modifier oxides and fluxing oxides which are activated to undesirable radionuclides when placed in a neutron beam, and requiring large numbers of microspheres in order to deliver the required amount of radiation to the target tissue.
There have been several reports of clinical studies on the use of solid glass radioactive microspheres. In one report, ten patients with primary hepatocellular carcinoma were treated, however no patient had a complete or partial response (Shepherd, F. et al., Cancer, Nov. 1, 1992, Vol.70, No.9, pp 2250–2254).
Another approach has been focussed on the use of small hollow or cup-shaped ceramic particles or microspheres, wherein the ceramic base material consists or comprises yttria or the like (see International Patent Application No. PCT/AU95/00027; WO 95/19841).